Extracellular calcium concentration is precisely regulated in the organism and one of the key elements of this regulation is the calcium receptor known as the Ca sensing receptor or CaSR. A receptor of this type at the surface of specific cells can detect the presence of calcium. Specific cells of the organism respond not only to chemical signals, but also to ions such as extracellular calcium ions (Ca2+): changes in the concentration of these extracellular Ca2+ ions can modify the functional responses of these cells. These cells include parathyroid cells which secrete the parathyroid hormone known as PTH. Parathyroid cells thus have at their surface the calcium receptor (CaSR), which detects changes in extracellular calcium concentration, and initiates the functional response of this cell, which is a modulation of the secretion of the parathyroid hormone (PTH). PTH, by acting in particular on the bone cells or on the renal cells, increases the calcium level in the blood. This increase then acts as a negative control on PTH secretion. The reciprocal relationship between calcium concentration and PTH level is an essential mechanism for calcium homeostasis maintenance.
The cloning of the calcium receptor by Brown in 1993 consequently demonstrated two possible signalling pathways for this G protein coupled receptor: one pathway by activation of the Gi protein (sensitive to the pertussis toxin) which stimulates phospholipase C and inhibits adenylate cyclase; the other pathway by activating the Gq protein responsible for mobilising intracellular calcium. These two signalling pathways, either independently of one another or together, can be activated so as to trigger the associated biological effect.
On its extracellular portion, the calcium receptor is a low affinity receptor which is stimulated by millimolar concentrations of agonists, in particular the calcium ion Ca2+. In addition, this receptor can also be activated by some divalent metals (magnesium) or trivalent metals (gadolinium, lanthanum, etc.) or else by polycationic compounds such as neomycin or spermin.
Novel compounds acting on the transmembrane portion of the receptor have been identified by Edward F. Nemeth et al (company NPS, U.S. Pat. No. 6,211,244) and allow the calcium receptor to be modulated allosterically. The action of first generation and second generation compounds on the pharmacological regulation of parathyroid hormone (PTH) secretion is described, for example, by E. F. Nemeth in Current Pharmaceutical Design, 2002, 8, 2077-2087. In particular, the compound AMG073 (cinacalcet, Sensipar®, Mimpara®) acts as an agonist of the calcium receptor and was first sold in the United States in 2004 for the treatment of secondary hyperparathyroidism (Idrugs, 2003, 6, 587-592 J. Iqbal, M. Zaidi, A. E. Schneider).